Uptravi Range 200 mg/400 mg/600 mg/800 mg/1000 mg/1200 mg/1400

UPTRAVI is indicated for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients with WHO functional class (FC) IIu2013IV to delay disease progression. Disease progression events included: death, hospitalisation for PAH, initiation of prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH-specific treatment). UPTRAVI is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

Posology
Individualised dose titration
The goal is to reach the individually appropriate dose for each patient (the individualised maintenance dose). The recommended starting dose of UPTRAVI is 200 micrograms given twice daily, approximately 12 hours apart. The dose is increased in increments of 200 micrograms given twice daily, usually at weekly intervals, until an acceptable maximum tolerated dose is achieved or adverse pharmacological effects that cannot be tolerated or medically managed are experienced, or until a maximum dose of 1 600 micrograms twice daily is reached. While a maximum with an acceptable tolerability is being determined, it is recommended not to discontinue treatment in the event of mild to moderate pharmacological side effects since they are usually transient or manageable with symptomatic treatment [see section 4.8]. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous dose level.

Individualised maintenance dose
The highest tolerated dose reached during dose titration should be maintained. If the therapy over time is less tolerated at a given dose, symptomatic treatment or a dose reduction to the next lower dose should be considered.

Interruptions and discontinuations
If a dose of medication is missed, it should be taken as soon as possible. The missed dose should not be taken if time for the next scheduled dose is within 6 hours. If treatment is missed for 3 days or more, UPTRAVI should be re-started at a lower dose and then titrated.

Dosage adjustment with co-administration of moderate CYP2C8 inhibitors
When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI to once daily. Revert back to twice daily dosing frequency of UPTRAVI when co-administration of moderate CYP2C8 inhibitor is stopped (see section 4.5).

Information about special populations
Paediatric use
Paediatric population (< 18 years)
The safety and efficacy of UPTRAVI in children have not been established.

Elderly use
Elderly (u2265 65 years)
No adjustment to the dosing regimen is needed in elderly patients.

Use in other populations
Renal impairment
No adjustment to the dosing regimen is needed in patients with mild or moderate renal impairment. No change in starting dose is required in patients with severe renal impairment. In patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1,73 m2) caution should be exercised during dose titration. There is no experience with UPTRAVI in patients undergoing dialysis.

Hepatic impairment
No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-Pugh class A). A once daily regimen is recommended in patients with moderate hepatic impairment (Child-Pugh class B) due to the increased exposure to UPTRAVI and its active metabolite in this population. There is no clinical experience with UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).

Method of administration
The film-coated tablets are to be taken orally in the morning and in the evening. UPTRAVI may be taken with or without food. Tolerability may be improved when taken with food. The tablets should not be split, crushed or chewed, and are to be swallowed with water.

• Hypersensitivity to the active substance, selexipag, or to any of the excipients listed in section 6.1.
• Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil, see section 4.5).

Hyperthyroidism
Hyperthyroidism has been observed with UPTRAVI. Thyroid function tests are recommended as clinically indicated.

Pulmonary veno-occlusive disease
Should signs of pulmonary oedema occur, consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, discontinue UPTRAVI.

Intolerance
UPTRAVI contains mannitol that may have a laxative effect or cause diarrhoea. Patients with the rare hereditary condition of mannitol intolerance should not take UPTRAVI.

Anticoagulants or inhibitors of platelet aggregation: Selexipag and its active metabolite inhibited platelet aggregation in vitro. In the Phase 3 placebo-controlled study in patients with PAH, no increased risk of bleeding was detected with selexipag compared to placebo, including when selexipag was administered with anticoagulants (such as heparin, coumarin-type anticoagulants) or inhibitors of platelet aggregation. In a study in healthy subjects, selexipag (400 micrograms twice a day) did not alter the exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 20 mg warfarin. Selexipag did not influence the pharmacodynamic effect of warfarin on the international normalised ratio. The pharmacokinetics of selexipag and its active metabolite were not affected by warfarin.

Interaction with other medicines: Selexipag is hydrolysed to its active metabolite by carboxylesterase (see section 5.2). Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the transporter breast cancer resistance protein (BCRP). Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes or transport proteins at clinically relevant concentrations.

Interaction with enzyme inhibitors: Lopinavir/ritonavir: In the presence of 400/100 mg lopinavir/ritonavir, twice a day, a strong CYP3A4, OATP (OATP1B1 and OATP1B3) and P-gp inhibitor, exposure to selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of selexipag did not change. Gemfibrozil: In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure to selexipag increased approximately 2-fold, whereas exposure to the active metabolite, increased approximately 11-fold. Concomitant administration of selexipag with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated (see section 4.3). Clopidogrel: Concomitant administration of selexipag with clopidogrel (300 mg as a loading dose or maintenance dose of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2, 2-fold and 2, 7-fold following loading dose and maintenance dose, respectively (see section 4.2).

Interaction with enzyme inducers: Rifampicin: In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 and UGT enzymes, the exposure to selexipag did not change whereas exposure to the active metabolite was reduced by half. Dose adjustment of UPTRAVI may be required.

Pharmacodynamic interactions: Reductions in blood pressure may occur when UPTRAVI is administered with diuretics, antihypertensive medicines, or other vasodilators.

Women of childbearing potential
Women of childbearing potential should practice effective contraception while taking UPTRAVI.

Pregnancy
Safety and/or efficacy in pregnancy has not been established. There are limited data on the use of UPTRAVI in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Breastfeeding
It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its metabolites are excreted in the milk (see section 5.3). Breastfeeding is not recommended during treatment with UPTRAVI.

Fertility
There are no clinical data available. In rat studies, selexipag at high doses caused transient disturbances in oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans is not known.

No studies on the effect of UPTRAVI on the ability to drive and use machines have been performed.

Summary of safety profile
The most commonly reported adverse reactions related to the pharmacological effects of UPTRAVI are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in the extremity, flushing, and arthralgia. These reactions are more frequent during the dose titration phase. The majority of these reactions are of mild to moderate intensity.

Tabulated list of adverse reactions
The safety of UPTRAVI has been evaluated in a long-term, Phase 3, placebo-controlled study enrolling 1 156 patients with symptomatic PAH. The mean treatment duration was 76,4 weeks (median 70,7 weeks) for patients receiving UPTRAVI versus 71,2 weeks (median 63,7 weeks) for patients on placebo. The exposure to UPTRAVI was up to 4,2 years.

Adverse drug reactions associated with UPTRAVI over the entire treatment period in this study are presented in the table below. Frequency is reported according to CIOMS: very common u2265 1/10, common u2265 1/100 to < 1/10, uncommon u2265 1/1 000 to < 1/100, rare (u2265 1/10 000 to < 1/1 000) and very rare (< 1/10 000).

Isolated cases of overdose up to 3 200 microgram were reported. The patient should be monitored for adverse events as per section 4.8. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound.